title: UPA promotes lipid-loaded vascular smooth muscle cell migration through LRP-1.
abstract: OBJECTIVE
  Migration of vascular smooth muscle cells (VSMCs) is a crucial event in atherosclerosis and vascular repair. Low-density lipoprotein (LDL) infiltrated in the vessel wall become aggregated (agLDL) and internalized by VSMC through the LDL receptor-related protein LRP1, deriving in lipid-loaded cells with reduced motility capacity. The urokinase-plasminogen activator (UPA)/UPA receptor (UPAR) system plays a relevant role in vascular remodelling. Here, we investigated whether UPA-ligand binding is involved in the detrimental effects of lipid loading in VSMC migration.
  
  
  RESULTS
  Animals fed a high-fat diet had 10-fold higher cholesterol-LDL plasma levels, >60% decrease in aortic UPA-protein expression, and VSMC showed impaired outgrowth from aortic explants. Angiotensin II infusion significantly increased aortic UPA expression and accelerated VSMC migration. Using an in vitro model of wound repair, we showed that agLDL inhibits UPA-mediated VSMC migration. UPA silencing reduced migration in control cells to levels observed in lipid-loaded VSMC. UPA silencing did not affect migration in lipid-loaded VSMC. UPA expression was significantly decreased in agLDL-exposed VSMC. agLDL also induced changes in the subcellular localization of UPA, with a reduction in colocalization with UPAR strongly evident at the front edge of agLDL-treated migrating cells. Rescue experiments showed that UPA acting as UPAR ligand restored migration capacity of agLDL-VSMC to control levels. The effects of UPA/UPAR on migration of lipid-loaded cells occurred through the binding to LRP-1.
  
  
  CONCLUSIONS
  UPA-ligand binding regulates VSMC migration, a process that is interfered by LDL. Thus, tissue infiltrated LDL through the abrogation of UPA function reduces VSMC-regulated vascular repair.
authors.affiliation: Cardiovascular Research Center , CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Av. S. Antoni M. Claret, 167, 08025 Barcelona, Spain.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lugano
authors.forename: Esther
authors.initials: E
authors.lastname: Peña
authors.forename: Laura
authors.initials: L
authors.lastname: Casani
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
authors.forename: Teresa
authors.initials: T
authors.lastname: Padró
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D006801:Humans; D006937:Hypercholesterolemia / Q000473:pathology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055293:Receptors, Urokinase Plasminogen Activator / Q000032:analysis; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*; D014945:Wound Healing
chemical_list: D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D055293:Receptors, Urokinase Plasminogen Activator; D000804:Angiotensin II; D014568:Urokinase-Type Plasminogen Activator
keywords: Cell migration; LDL; LRP-1; Urokinase–plasminogen activator; Vascular smooth muscle cells